This invention concerns multi-layered, controlled releasing drug beads, their preparation, and pharmaceutical use.
It is desirable to formulate orally delivered drugs in a manner which permits administration on a once or twice per day schedule to facilitate patient compliance and to reduce swings in blood plasma levels. However, it is difficult to achieve the desired therapeutic blood levels of many drugs, such as those which are rapidly absorbed into the bloodstream or those which are readily metabolized, without a more frequent dosing schedule. Desired blood levels of some of these drugs, however, can be obtained by formulating the drugs in a manner which delays or sustains the release of the drug.
Sustained release pharmaceutical preparations utilized to delay the release of a drug in the digestive tract include those in which the active substance is embedded within a polymeric matrix which dissolves extremely slowly. The drug is bound within the polymeric matrix and is gradually released as the matrix dissolves. In another type of delayed-release formulation, the active substance is shaped into beads or tablets and a sustained release coating is applied to slow the release of the active substance. The sustained release coating may be one which is soluble or it may be insoluble but permeable to an aqueous medium.
These conventional types of sustained release formulations can be effective to provide the desired release rates for some types of drugs, including those which are readily absorbed and/or metabolized. The human digestive tract, however, has pH values ranging from 1.0 to 7.5 and adequate blood levels of many types of drugs are difficult to achieve, even with such sustained release formulations. For example, drugs which are weak bases are solubilized and absorbed only if the solid pharmaceutical preparation remains in the acidic range for a sufficient time period. Absorption of such drugs thus depends greatly upon the retention time and the pH in the patient's stomach and upper intestine.
In order to obtain a pH independent release for drugs having pH dependent solubility characteristics, it has been suggested that the sustained release drug pellets or tablets include an acid buffer to provide the desired pH within the pellets regardless of the pH of the surrounding aqueous medium. It has proven difficult, however, to maintain the acid buffer for the time period necessary to achieve complete release of the drug from the pellets or tablet.
What is lacking and needed in the art is a controlled and pH independent release formulation which can be used for oral delivery of pharmaceuticals, particularly those pharmaceuticals which are generally soluble only in acidic mediums, and which is suitable for administration at infrequent intervals such as once or twice a day.